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Process for the preparation of asenapine

a technology of asenapine and process, which is applied in the field of new compounds of formula i, can solve the problems of only moderate final yield of trans-isomer, complex and time-consuming, etc., and achieve good esteroselectivity and yield. good

Active Publication Date: 2014-02-18
INKE SA (ES)
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  • Abstract
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  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a process for making asenapine with a high yield, which is suitable for industrial scale production. The process involves reacting an amino alcohol compound with a formic acid anhydride or a chloroformate, optionally converting the hydroxyl moiety into a leaving group, cyclizing the compound, and optionally converting it to a salt. The invention also includes a process for making the amino alcohol compound using a reducing agent. The invention also utilizes novel intermediates and compound II in the preparation of asenapine and its salts.

Problems solved by technology

The drawback of this process is that it is extremely elaborate and time-consuming, while the final yield of the trans-isomer is only moderate.

Method used

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  • Process for the preparation of asenapine
  • Process for the preparation of asenapine
  • Process for the preparation of asenapine

Examples

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example 1

Preparation of trans-(11-Aminomethyl-2-chloro-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-methanol (5)

[0132]

[0133]A solution of trans-2-Chloro-11-nitromethyl-10,11-dihydro-dibenzo[b,f]oxepine-10-carboxylic acid methyl ester (4) (4.6 g, 13.23 mmol) in dry THF (23 ml) is added at—15° C. to a mixture of THF (23 ml) and 3.5 M Lithium aluminum hydride (LAH) suspension in THF / Toluene (15.1 ml, 52.9 mmol).

[0134]The mixture is stirred at 30° C. for 30 minutes, cooled to −15° C. and sequentially quenched with H2O (2 ml), 15% NaOH (2 ml) and H2O (6 ml).

[0135]The solid is filtered, washed with THF (2×23 ml) and the filtrate evaporated to dryness to give 3.60 g (95%) of trans-(11-Aminomethyl-2-chloro-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-methanol (5) as a pale yellow solid.

[0136]1-H-RMN (CDCl3, 200 MHz): 1.64 (br s, 3H, exchg. D2O), 2.70-2.80 (m, 1H) 2.87-2.97 (m, 1H), 3.12-3.18 (m, 1H) 3.19-3.36 (m, 1H), 3.44-3.54 (m, 1H), 3.63-3.72 (m, 1H), 7.03-7.26 (m, 7H).

example 2

Preparation of trans-N-(8-Chloro-11-hydroxymethyl-10,11-dihydro-dibenzo[b,f]oxepin-10-ylmethyl)-formamide (6)

[0137]

[0138]A mixture of Acetic Anhydride (2 ml, 20.7 mmol) and Formic Acid (1.6 ml, 41.4 mmol) is heated to 50° C. for 2 hours. After cooling to 25° C. the mixture is diluted with dichloromethane (15 ml). Next, reaction is cooled to 0° C. and trans-(11-Aminomethyl-2-chloro-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-methanol (5) (3.00 g, 10.4 mmol) is added and is stirred at 25° C. for one hour.

[0139]Reaction is quenched with 10% K2CO3 (20 ml) and organic layer is washed with 10% K2CO3 until pH 9.

[0140]Methanol (3 ml) and solid K2CO3 (0.72 g, 5.21 mmol) are added to the organic layer and stirred for 2 hours at room temperature (r.t.). Water (30 ml) is then added and stirred for additional 15 min. Organic layer is then separated, washed with water (2×20 ml) and brine (20 ml) and evaporated to dryness to give 2.45 g (76%) of trans-N-(8-Chloro-11-hydroxymethyl-10,11-dihydro-dibenzo...

example 3

Preparation of trans-(2-Chloro-11-methylaminomethyl-10,11-dihydro-dibenzo[b,f]oxepin-10-yl)-methanol (7)

[0142]

[0143]Sodium Borohydride (0.80 g, 21.2 mmol) is added at 0° C. to a solution of trans-N-(8-Chloro-11-hydroxymethyl-10,11-dihydro-dibenzo[b,f]oxepin-10-ylmethyl)-formamide (6) (2.25 g, 7.1 mmol) in dry THF (15 ml). The mixture is stirred for 10′. Next Boron trifluoride tetrahydrofuran complex (4 ml, 34.6 mmol) is added dropwise maintaining temperature below 5° C. Reaction is then stirred at 35° C. for 15 h.

[0144]Reaction is then cooled to 0° C. and 3N HCl (15 ml) is added, then is heated to 100° C. and stirred for 30 minutes, during heating about 15 ml of tetrahydrofuran are distilled.

[0145]Next is cooled to room temperature and 10% K2CO3 is added until pH 9, followed by ethyl acetate (30 ml). Organic layer is separated and washed with water, 1M NaOH and brine and evaporated to dryness to obtain 1.85 g (87%) of trans-(2-Chloro-11-methylaminomethyl-10,11-dihydro-dibenzo[b,f]ox...

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Abstract

The present invention is directed to novel compounds of formula (I) as well as to the process for their preparation. Novel compounds of formula (I) can be converted into asenapine through an efficient process. The invention also relates to novel intermediates used in this process and their use in the preparation of compounds of formula (I).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a national stage entry under 35 U.S.C. §371(b) of International Application No. PCT / EP2011 / 063071, filed Jul. 29, 2011, which claims the benefit of European Patent Application Serial No. 10171222.2, filed Jul. 29, 2010 and U.S. Provisional Application Ser. No. 61 / 370,506, filed Aug. 4, 2010, the disclosures of all of which are hereby incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention is directed to novel compounds of formula I and their use as intermediates in the synthesis of asenapine. The invention provides a process for the preparation of these novel compounds of formula I and their conversion to asenapine.BACKGROUND OF THE INVENTION[0003]Asenapine or trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole is described in U.S. Pat. No. 4,145,434 to van der Burg and it is represented by the following chemical structure:[0004][0005]Asenapine has CNS-depres...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D313/14C07D491/044
CPCC07D491/04C07D491/044C07D313/14A61P25/00A61P25/18A61P25/24A61K31/335
Inventor DALMASES BARJOAN, PEREHUGUET CLOTET, JUANPEIRATS MASIA, JORDI
Owner INKE SA (ES)
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